Clinical, epidemiologic, genetic, and experimental studies have demonstrated that diabetes mellitus is a heterogeneous group of disorders rather than a single disease. The objective of this project is to demonstrate some of the genetic heterogeneity of diabetes at a cellular level, using cultured skin fibroblasts as a model system. Cultures will be initiated from patients with various types of diabetes, including juvenile- and maturity-onset types, the maturity-onset diabetes of young, and mendelian diseases associated with glucose intolerance. Insulin responsiveness will be assessed by studying the hormo stimulation of amino acid transport in serum-starved cells. The effect of incubation of the cells with glucocorticoids and oral hypoglycemic agents on their insulin responsiveness will also be studied. Insulin binding to fibroblasts will be assessed using radiolabelled hormone. It is hoped that these approaches will demonstrate differences in the pattern of in vitro insulin responsiveness which reflect the clinical and genetic differences observed in vivo. The validity of these cellular markers of genetic heterogeneity will be tested by examining fibroblast cultures from both affected and unaffected members of families with specific subtypes of diabetes.